Lactonization process

ABSTRACT

Crystalline 3-hydroxylactone-containing products can be prepared in high yield and purity in a one-pot process by treating the corresponding 3,5-dihydroxy acid with a strong mineral acid in a cold, aprotic, water-miscible solvent to effect lactonization, followed by addition of excess acid to effect crystallization of the lactonized product from the reaction mixture.

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/161,876, filed Oct. 27, 1999 which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention involves a lactonization process which isuseful for making 3-hydroxy lactone-containing products, such as3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors.

BACKGROUND OF THE INVENTION

[0003] It has been clear for several decades that elevated bloodcholesterol is a major risk factor for coronary heart disease (CHD), andmany studies have shown that the risk of CHD events can be reduced bylipid-lowering therapy. Prior to 1987, the lipid-lowering armamentariumwas limited essentially to a low saturated fat and cholesterol diet, thebile acid sequestrants (cholestyramine and colestipol), nicotinic acid(niacin), the fibrates and probucol. Unfortunately, all of thesetreatments have limited efficacy or tolerability, or both. With theintroduction of lovastatin (MEVACOR®; see U.S. Pat. No. 4,231,938), thefirst inhibitor of HMG-CoA reductase to become available forprescription in 1987, for the first time physicians were able to obtaincomparatively large reductions in plasma cholesterol with very fewadverse effects.

[0004] In addition to the HMG-CoA reductase inhibitors which are naturalfermentation products, mevastatin and lovastatin, there are now avariety of semi-synthetic and totally synthetic analogs thereof,including simvastatin (ZOCOR®; see U.S. Pat. No. 4,444,784), pravastatin(PRAVACHOL®; see U.S. Pat. No. 4,346,227), fluvastatin (LESCOL®; seeU.S. Pat. No. 5,354,772), atorvastatin (LIPITOR®; see U.S. Pat. No.5,273,995), cerivastatin (also known as rivastatin; see U.S. Pat. No.5,177,080) and nisvastatin (also known as NK-104, see U.S. Pat. Nos.5,284,953, 5,356,896 and 5,856,336). The hemi-calcium salt ofnisvastatin is described and claimed in U.S. Pat. No. 5,856,336, whilethe structural formulas of the other noted HMG-CoA reductase inhibitors,as well as additional examples of HNG-CoA reductase inhibitors, aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (Feb. 5, 1996). The HMG-CoA reductaseinhibitors described above belong to a structural class of compoundswhich contain a moiety which can exist as either a 3-hydroxy lactonering or as the corresponding open-ring 3,5-dihydroxy acid, as depictedbelow in the Scheme, and are commonly referred to as “statins.”

[0005] The lactonized forms of the statins are metabolized to the activeopen-ring 3,5-dihydroxy acid form in the body. Lovastatin andsimvastatin are marketed worldwide in their lactonized form. However,the preparation of the naturally occurring compounds and theirsemi-synthetic analogs leads to a mixture of the lactone and theopen-ring 3,5-dihydroxy acid forms. Therefore, it is important to employa high yielding and efficient method for lactonizing the open-ring formor a salt thereof.

[0006] Since lactonization is an equilibrium reaction, as illustrated inthe Scheme below, some means of shifting the equilibrium to the “right,”i.e., towards formation of the lactone, is required to achieve productin high yield and high purity.

[0007] In previous published procedures for making 3-hydroxylactone-containing HNG-CoA reductase inhibitors, this equilibriumreaction was driven toward lactone formation by either (1) heating thedihydroxy acid in a neutral solvent with continuous removal of the waterby-product, see U.S. Pat. No. 4,444,784, or by (2) removing the lactoneproduct by adding water in order to crystallize out the lactone product,see U.S. Pat. No. 4,916,239.

[0008] When applying the technique of water removal to drive theequilibrium toward the desired lactone product, higher temperatures arerequired which promote an undesirable esterification reaction betweenthe 3-hydroxy group of the 3-hydroxylactone with the precursor free acidto produce a dimeric impurity. As an example, the dimer of simvastatinis shown below. Reduction of the dimer impurity content in the finalproduct is difficult, since standard purification methods such asre-crystallization, which requires heating, tend to promote furtherdimer formation.

[0009] Applying the approach of adding water to the reaction mixture todrive the equilibrium toward the lactone product mitigates the dimerimpurity problem, but two other problems occur with this procedure. Oneproblem is that the addition of water to effect crystallization of theproduct and drive the equilibrium toward the lactone side providesinsufficient force to take the reaction to completion, resulting incontamination of the final product with unconverted starting material.This requires an additional purification step to produce a high purityproduct. A second problem is that when a water-miscible protic solventsuch as acetic acid is used for the lactonization as is taught in U.S.Pat. No. 4,916,239, an esterification reaction between the solvent andthe 3-hydroxy group of the 3-hydroxylactone occurs to produce3-O-acylated lactone and corresponding 3-O-acylated open-ring 5-hydroxyacid side-product impurities which are not effectively removed, evenafter a subsequent purification step.

[0010] The instant invention provides a novel single-potlactonization/purification process that can be used to produce 3-hydroxylactone containing products, including statins, that avoids theaforementioned problems and provides a higher quality lactone producthaving a lower amount of total impurity than previously possible on acommercial scale. Particularly, all 3-O-acylated lactone and3-O-acylated open-ring sideproduct impurities are eliminated. Inaddition, when the procedure is performed at sufficiently coldtemperatures, the amount of dimer impurity in the final product measuredby analytical BPLC as an area percentage is 0.1 area % or less.Therefore, the instant process eliminates the need for a separatepurification step. The novel process described herein also results in abetter yield and greater throughput in a single step.

SUMMARY OF THE INVENTION

[0011] One object of this invention is to provide an improvedlactonization and purification process for making 3-hydroxylactone-containing products in high yield using strong mineral acid toeffect the lactonization and precipitation of the final product.

[0012] A second object is to employ the instant process for thepreparation of 3-hydroxy lactone-containing HMG-CoA reductase inhibitorsof the statin crass.

[0013] A third object is to employ the process using a water-miscible,polar, aprotic solvent thereby eliminating the formation of any3-O-acylated lactone or 3-O-acylated open-ring side-product impurities.

[0014] A fourth object is to employ the process at sufficiently coldtemperatures in order to decrease any dimer side-product impurity thatforms to 0.20 area % or less, as quantified by analytical HPLC.

[0015] A fifth object is to employ the instant process under conditionsso as to reduce the level of any single impurity that is present in thefinal product to 0.1 area % or less, as quantified by analytical HPLC.

[0016] A sixth object is to provide a process that can be adapted to beefficiently run on a large, factory scale.

[0017] A seventh object is to provide a commercial scale compositioncomprised of a 3-hydroxy lactone-containing product, for example astatin, and specific, reduced levels of chemical impurities that arepresent in the product. Additional objects will be evident from thefollowing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0018] This invention is concerned with a novel process that can beperformed in one pot for preparing a 3-hydroxy lactone-containingproduct from its corresponding open-ring 3,5-dihydroxy acid or a saltthereof.

[0019] The novel process for preparing a 3-hydroxy lactone-containingproduct from a salt of its corresponding open-ring 3,5-dihydroxy acidcomprises the steps of:

[0020] (i) adding a strong mineral acid to a stirring suspension of thesalt of a 3,5-dihydroxy acid-containing compound in a water-miscibleorganic solvent in an amount sufficient to protonate the salt and formthe corresponding 3,5-dihydroxy acid;

[0021] (ii) adding additional strong mineral acid to the stirringsolution of the 3,5- dihydroxy acid in an amount sufficient to lactonizethe 3,5-dihydroxy acid to form a 3-hydroxy lactone-containing product;

[0022] (iii) adding an excess of additional strong mineral acid to thestirring reaction mixture in an amount sufficient to causecrystallization of the 3-hydroxy lactone-containing product;

[0023] (iv) collecting and washing the 3-hydroxy lactone-containingproduct; and

[0024] (v) drying the washed 3-hydroxy lactone-containing product.

[0025] This one-pot process is illustrated in the Flow Sheet, below,wherein X is a salt-forming cation, and Y represents the chemicalstructural remainder of the 3,5-dihydroxy acid-containing compound andthe 3-hydroxy lactone-containing product, as appropriate. Y can be anysuitable chemical moiety that is amenable to the reaction conditions ofthe instant lactonization process.

[0026] FLOW SHEET

[0027] The process of this invention has been described above asproceeding from salt (I) to acid (II) to lactone (III). Clearly, if theacid (II) is available for use as starting material, this inventionincludes, as one embodiment, the process of proceeding from acid (II) tolactone (III) and isolation of the lactone.

[0028] This process can be used to prepare, in one pot, highly purified3-hydroxy lactone-containing compounds from the class of 3,5-dihydroxyacid-containing compounds or from salts thereof without the need for anadditional purification procedure. In a second embodiment of thisinvention, the 3-hydroxy lactone-containing products are statins whichhave activity as HMG-CoA reductase inhibitors. One class of lactonizedstatins within this embodiment includes lovastatin and simvastatin.Additional members of this class include but are not limited to thelactonized forms of pravastatin, fluvastatin, atorvastatin, cerivastatinand nisvastatin.

[0029] An alternate class of compounds within this second embodimentincludes 3,5-dihydroxy acids, or salts thereof, useful as startingmaterials and the corresponding lactonized products as defined byformulas I, II and III (see Flow Sheet) wherein Y is a member selectedfrom the group consisting of

[0030] wherein R is selected from —OH and —CH₃; and R′ is C₁₋₁₀alkyl.

[0031] A sub-class of compounds within this alternate class are thosewherein Y is a member selected from the group consisting of:

[0032] wherein R is selected from —OH and —CH₃.

[0033] A specific member of this sub-class is that wherein Y is

[0034] the lactonized form (formula III) of this specific member issimvastatin.

[0035] The starting material for the instant lactonization process isthe desired lactone product's corresponding 3,5-dihydroxy acid or a saltthereof which is converted to the free acid prior to lactonization, asdepicted in the Flow Sheet above, wherein X is any suitable salt-formingcation, including but not limited to those formed from such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as from amines such as ammonia,ethylenediamine, N-methylglucamine, lysine, arginine, ornithine,β-choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine,procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenzimidazole, diethylamine,piperazine, and tris(hydroxymethyl)aminomethane. A specific member ofthe class of salt forming cations is ammonium.

[0036] As used herein “alkyl” is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl,butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl and the isomersthereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu),tertbutyl (t-Bu), isopentyl, isohexyl and the like. The term “alkyl”includes both unsubstituted and substituted alkyl groups, for examplemono-, di- and tri-substituted alkyl groups; one example is a benzylgroup, wherein the aryl ring of the benzyl group may also beunsubstituted or substituted.

[0037] The term “dimer” or “dimeric impurity” as used herein is intendedto include any esterification products that result from the reactionbetween the 3-hydroxy group of a 3-hydroxy lactone-containing compoundand the free acid of a 3,5-dihydroxy acid-containing compound.Particularly, such dimers include the coupled statin dimers. Specificexamples of compounds which are encompassed by the term dimer include,but are not limited to, the simvastatin dimer depicted above, and theanalogous lovastatin dimer. The term dimer also includes the productsformed by an esterification reaction between two different statins, forexample the dimer product resulting from the reaction of the 3—OH groupof simvastatin with 3,5-dihydroxy acid lovastatin (referred to herein as3-O-mevinolinyl simvastatin), or alternately the reaction of the 3—OHgroup of lovastatin with 3,5-dihydroxy simvastatin. Analogous dimersresulting from other statins are readily envisioned and similarlyencompassed.

[0038] The term “3-O-acylated impurities” as used herein is intended toinclude the side-product impurities formed by the esterificationreaction between a carboxy-acid containing solvent and the 3-hydroxygroup on the lactone or the 3-hydroxy group on the correspondingopen-ring 3,5-dihydroxy acid, resulting in a 3-O-acyl group wherein theacyl group has the formula C₁₋₁₀—C(O)—. As used herein, the term“3-O-acylated impurities” does not include dimeric impurities. Oneexample includes, but is not limited to, the 3-O-acylated sideproductimpurities derived from acetic acid, as depicted below,

[0039] and particularly may be 3-O-acetyl simvastatin and thecorresponding 3-O-acetyl open-ring simvastatin.

[0040] The term “area %” as used herein is intended to be a unit ofmeasurement for defining an indicated amount of a component compoundcontained in a composition. More specifically, the area % is the percent composition determined by measuring the area of each peak anddividing the individual areas by the total area as determined byanalytical HPLC, and particularly using the HPLC method defined inExample 4 herein. The formula for determining area % is represented as:

area %=(area of component /total area of all components)×100.

[0041] The term “composition” as used herein is intended to be a solidchemical composition comprised of a 3-hydroxy lactone-containingproduct, for example a statin, and the chemical impurities that arepresent in the product. Impurities are intended to include undesiredside-products formed in the reaction process. Examples of chemicalimpurities that may be present in the 3-hydroxy lactone-containingproduct include but are not limited to dimeric impurities (also referredto herein as dimer), and 3-O-acylated lactone and 3-O-acylated open-ringimpurities. For example, certain impurities, which may be found in asimvastatin composition, depending on the process used to make thesimvastatin, are listed in Example 4 herein.

[0042] The term “commercial scale composition” as used herein isintended to mean a commercial scale quantity of a composition which isproduced as a single batch of at least 100 g of the composition.Embodiments of this invention include a commercial scale compositionthat is produced as a single batch of at least 100 g of the compositionwhich has not been subjected to HPLC (high pressure liquidchromatography) purification, and a commercial scale composition that isproduced as a single batch of at least 100 g of the composition whichhas not been subjected to any purification procedure. Examples includebut are not limited to commercial scale compositions which are producedas a single batch of at least 100 g, at least 500 g, and at least onekilogram of the composition.

[0043] Another embodiment is a commercial scale composition comprised ofa 3-hydroxy lactone-containing product absent 3-O-acylated impurities,and 0.20 area % or less of dimeric impurity. A particular exampleincludes but is not limited to a commercial scale composition comprisedof a 3-hydroxy lactone-containing product absent 3-O-acylatedimpurities, and 0.20 to 0.01 area % dimeric impurity.

[0044] Within this embodiment is a commercial scale compositioncomprised of a 3-hydroxy lactone-containing product absent 3-O-acylatedimpurities, and 0.1 area % or less of dimeric impurity. A particularexample includes but is not limited to a commercial scale compositioncomprised of a 3-hydroxy lactone-containing product absent 3-O-acylatedimpurities, and 0.1 to 0.01 area % of dimeric impurity.

[0045] Also within this embodiment is a commercial scale compositioncomprised of a 3-hydroxy lactone-containing product absent 3-O-acylatedimpurities, 0.1 area % or less of dimeric impurity, and 0.1 area % orless of each of the other impurities present in the composition. Aparticular example includes but is not limited to a commercial scalecomposition comprised of a 3-hydroxy lactone-containing product absent3-O-acylated impurities, 0.1 to 0.01 area % of dimeric impurity, and 0.1to 0.01 area % of each of the other impurities present in thecomposition.

[0046] Further within this embodiment is a commercial scale compositioncomprised of a 3-hydroxy lactone-containing product absent 3-O-acylatedimpurities, 0.1 area % or less of dimeric impurity, 0.1 area % or lessof 3-exomethylene simvastatin, and 0.10 area % or less of each of theother impurities present in the composition. A particular exampleincludes but is not limited to a commercial scale composition comprisedof a 3-hydroxy lactone-containing product absent 3-O-acylatedimpurities, 0.1 to 0.01 area % of dimeric impurity, 0.1 to 0.01 area %of 3-exomethylene simvastatin, and 0.10 to 0.01 area % of each of theother impurities present in the composition.

[0047] Also encompassed are any of the above-described commercial scalecompositions comprised of 0.10 area % or less of dimeric impurity, forexample but not limited to 0.10 to 0.01 area % of dimeric impurity. Thephrase “absent 3-O-acylated impurities” as used herein includes forexample 0.00 area % of 3-O-acylated impurities. Particularly, the3-hydroxy lactone-containing product in the commercial scale compositionis a statin, and even more particularly simvastatin. The 3-O-acyl groupon the 3-O-acylated impurities may particularly be 3-O-acetyl.

[0048] The lactone product can be obtained using any suitablewater-miscible aprotic or protic organic solvent. However, use of aprotic solvent such as acetic acid or an alcohol leads to the problemsof side-product formation from esterification reactions between thesolvent and the 3-hydroxy group of the 3-hydroxylactone or the acidgroup of the dihydroxy acid precursor. An advantage of the claimedprocess is that all steps can be run in a water-miscible aprotic organicsolvent, which completely avoids the formation of any 3-O-acylatedside-product impurities. Members of the class of useful water-miscibleaprotic solvents include but are not limited to acetonitrile,dimethylsulfoxide (DMSO), dimethyl formamide (DMF), tetrahydrofuran(TBF), dioxane, and the like. A specific member of this class isacetonitrile.

[0049] The volume of aprotic solvent to be used should be at leastsufficient to dissolve the 3,5-dihydroxy acid and lactone product, butnot so great that inordinate volumes of strong mineral acid are requiredto cause crystallization of the lactone. Usually, volumes of about 4L toabout 6L of aprotic solvent per kilogram of dihydroxy acid salt areappropriate.

[0050] Vigorous stirring of the reaction mixture during each addition ofstrong mineral acid should be maintained throughout the process.Sub-surface addition of strong mineral acid to the vigorously stirredreaction mixture is preferred. Vigorous stirring leads to larger crystalsize and less occlusion of solvent and acid by the crystals.

[0051] The present process provides an advantage over previouslactonization processes in that the greater reactivity, lower lactoneproduct solubility and greater freezing point depression provided by theuse of strong mineral acid to drive the equilibrium, allow the reactionto be run at low temperatures, thus limiting undesired side reactions.Although not necessary, it is preferable that the steps of the process,from the salt protonation step up to and including the collection andwashing of the final product, be performed at a temperature of 10° C. orlower. One range of temperatures is from about 10° C. to about −15° C. Asecond range of temperatures is from about −8° C. to about −15° C. Thisnovel process remains useful for making lactonized products if run attemperatures above 10° C.; however, the purity of the product willprogressively suffer as the reaction temperature elevates, since theformation of a difficult to remove dimeric impurity increases as thetemperature increases. As discussed above, the dimer is a side-productimpurity that forms from an esterification reaction between the3-hydroxyl group of the 3-hydroxy lactone product and the precursor freeacid. It has been found that when practicing this process at reactiontemperatures above about 10° C., the dimeric impurity begins to riseabove about 0.2 area % in the final product, while at temperatures of10° C. and lower, the dimeric impurity can be kept to about 0.2 area %or less in the final product. The most preferred temperature range of−8° C. to −15° C. provides the least amount of dimer formation, that is,0.10 area % or less dimeric impurity in the final product.

[0052] Any strong mineral acid generally known to those of average skillin the art may be used with the present process. For optimum convenienceand efficiency, it is desirable to use the same strong mineral acid foreach of the protonation, lactonization and crystallization steps.However, the strong mineral acid need not be the same in each step inorder to obtain the desired product. Examples of strong mineral acidsthat may be used include but are not limited to HCl, HBr, perfluoricacid, perchloric acid, phosphoric acid and nitric acid. An example ofthe class of strong mineral acids is HCl. As will be appreciated bythose skilled in the art, the concentration of the strong mineral acidthat can be used in the process of this invention can vary. For example,the concentration of strong mineral acid may efficiently range fromabout 2N to about 6N, and illustratively about 4N, although otherconcentrations can be employed..

[0053] The amount of strong mineral acid useful in the process of thisinvention includes about 0.8 to 1.1 equivalents of strong mineral acidfor each equivalent of 3,5-dihydroxy acid salt to effect protonation ofthe carboxylate salt, plus about 0.8 to about 1.1 equivalents additionalstrong mineral acid to effect ring closure. An excess of strong mineralacid is used to promote crystallization of the lactonized product fromsolution; an excess as used herein is intended to mean greater than oneequivalent of mineral acid per equivalent of lactone product. Moreparticularly, from about 2 to about 5 equivalents of strong mineral acidis useful to drive the reactive crystallization. Therefore, a total ofabout 4 to about 7 equivalents of acid may be used for the entireprocess. In addition, the reaction mixture may optionally be seeded atthe crystallization step using standard techniques in the art to promotecrystal formation.

[0054] Depending on the quality of the starting material it is sometimesappropriate to treat the solution of the 3,5-dihydroxy acid in solventwith decolorizing carbon followed by removal of the carbon beforeproceeding with the lactonization step. The temperature should bemaintained within the cited ranges to assure the desired yield andpurity.

[0055] The last steps of the process of this invention comprise theisolation (also referred to herein as collecting), washing and drying ofthe final product. Any means of separating solids from liquids can beemployed for the isolation. However, for the scale exemplified herein itis convenient to pump the slurry of prod solvent into a centrifuge andfollow it with washes. The washes can consist of a water miscibleorganic solvent described above or water or mixtures thereof, preferablyat a temperature of 10° C. or lower as noted above. At this point, thewashed product can be aged for an extended period of time at atemperature of about 15° C. to 20° C. However, maximum yields andminimum amounts of 3,5-dihydroxy acid impurity are obtained if the finalwash is about 0.1N to about 0.5N in strong mineral acid, particularly0.1N and more particularly 0.1N HCl, followed by drying of the recoveredmaterial in a temperature range of about 35° C. to 50° C., andparticularly at about 40° C.

[0056] In the Examples below, the following abbreviations are used: SASsimvastatin ammonium salt BHA butylated hydroxyanisole O/N over nightMeCN acetonitrile MeOH methanol RT room temperature

EXAMPLE 1

[0057] Acetonitrile (40 mL) and butylated hydroxyanisole (BHA, 50 mg)were added to a 250 mL, 3-neck round bottom flask under a nitrogenatmosphere. The temperature was adjusted to −12° C. and simvastatinammonium salt (10.34 g, 22.8 mmol) was then added, while maintaininggood agitation. The ammonium salt was then protonated with oneequivalent of cold (−12° C.) hydrochloric acid (4N, 5.7 mL) by addingthe acid in subsurface manner at the tip of the impeller over 15minutes, while maintaining the temperature at −12° C. The resultingsolution was carbon treated (0.2 g), aged for three hours at −12° C. andfiltered to remove the carbon and any extraneous matter that may bepresent. A second equivalent of HCl was then added, as above (−12° C.,subsurface, 15 minutes). The reaction mixture was then seeded and theproduct crystallized over a five hour period by subsurface addition ofHCl (4N, 60 mL), maintaining the above temperature. The product wasisolated by filtration, washed with 1:1 methanol-0.1N HCl and driedunder vacuum (50 mm Hg; 35° C.). Yield 97.3%; purity by HPLC 99.6%.

EXAMPLE 2

[0058] Acetonitrile (40 mL)and BHA (50 mg) were added to a 250 mL,3-neck round bottom flask under a nitrogen atmosphere. The temperaturewas then adjusted to −12° C. and simvastatin ammonium salt (10.3 g, 22.8mmol) was added, while maintaining good agitation, followed by additionof cold (−12° C.) hydrochloric acid (48%, 5 mL, 44.2 mmol) over 15minutes, maintaining the temperature at −12° C. When dissolution wascomplete, hydrochloric acid (4N, 30 mL) was added in one portion. thereaction mixture was then seeded with pure simvastatin (50 mg) and thepure simvastatin product crystallized by subsurface addition ofhydrochloric acid (4N, 12 hours). The product was filtered, washed withcold (−12° C.) 1:1 methanol/0.1N HCl, and vacuum dried (50 mm Hg; 30-35°C., 12 hours). Yield 97.1%; Purity by HPLC 99.5%.

EXAMPLE 3

[0059] Acetonitrile (4 L) and BHA (5 g) were added to a 16-liter,full-jacket, cylindrical, glass reactor under a nitrogen atmosphere andthe solution cooled to −13° C. Simvastatin ammonium salt (1000 g, 2.2mol) was then added while maintaining good mixing using an agitatorcontaining two 45° pitched-four-bladed turbines (diameter 4.5 inches)set at an agitation rate of 250 rpm. The ammonium salt was thenprotonated by adding 500 mL cold (−13° C.) 4N HCl in one shot.Additional cold 4N HCl (3.5L) was then added subsurface over an eighthour period; the reaction mixture was seeded with pure simvastatin (20g) after having added 1.5L of the acid. Additional 4N HCL (4L) was nextadded in the same manner over a four hour period. Following thecrystallization with this last acid addition, the reaction mixture wasaged at −15° C. for one hour. The product was isolated bycentrifugation, washed with 1L of 30% aqueous acetonitrile at RT,followed by 2L of 1:1 MeOH/H₂O adjusted to 0.1N in HCl at −10° C., thendried in a rotary vacuum dryer for 7 hours at 45° C. and 25 mm Hgpressure. Yield 98%; purity by HPLC 99.6%.

[0060] In the foregoing Examples, the lactonization yields weretypically 98% and the purities equal to or greater than 99.6% with nosingle impurity greater than 0.1%. These purity values are better thanthose generated with the prior process of adding water to the reactionmixture in order to crystallize out the lactone product.

EXAMPLE 4

[0061] I. Analytical Method—HPLC (High Performance LiquidChromatography)

[0062] A. Reagents

[0063] 1. Water

[0064] 2. Acetonitrile (ACN)

[0065] 3. Phosphoric Acid (H₃PO₄)

[0066] 4. Potassium Phosphate Monobasic (KH₂PO₄)

[0067] 5. Simvastatin Reference Standard

[0068] B. Solutions

[0069] 1. Mobile Phase A—Add 1.0 mL of H₃PO₄ into a 1L volumetric flaskcontaining about 300 mL of water. Dilute to volume with water and mix.Mix this solution with 1L of acetonitrile and filter/degas prior to use.

[0070] 2. Mobile Phase B—Add 1.0 mL of H₃PO₄ into a 1L volumetric flaskcontaining about 300 mL of acetonitrile. Dilute to volume withacetonitrile and mix.

[0071] 3. Diluent—Dissolve 0.055 g of KH₂PO₄ in 400 mL of water. Adjustthe pH to 4.0 with phosphoric acid. Mix this solution with 600 mL ofacetonitrile and filter prior to use.

[0072] C. Chromatographic Conditions

[0073] To minimize system dead volume, all connections from the autosampler to the column and the column to the detector should be with0.007 inch I.D. tubing, with no single piece longer than 10 cm. Column:Perkin-Elmer Pecosphere cartridge, C18 CR. 33 mm × 4.6 I.D., 3 μmparticles inserted in a 3.3 cm cartridge holder. Flow Rate: 3.0mL/minute Temperature: Ambient Detection: 200 nm & 238 nm InjectionVol.: 25 μL & 5 μL Run Time: 13 minutes Gradient: Time (min) % A % B 0.0100 0 4.5 100 0 4.6  95 5 8.0  25 75  11.5  25 75  11.6 100 0 13.0 100 0

[0074] II. Using the Analytical HPLC method described above, thefollowing relative retention times were observed to be associated withthe listed simvastatin impurities. Impurity Relative Retention Time(RRT) 5-Hydroxyacid Simvastatin 0.447 (Open-ring Simvastatin) Lovastatin0.635 3-Exomethylene Simvastatin 0.810 Simvastatin Methyl Ester 1.100Dihydrosimvastatin 1.260 3-0-Acetyl Simvastatin 2.590 Dehydrosimvastatin2.669 3-0-Mevinolinyl Simvastatin 3.945 Simvastatin Dimer 4.455

3-Exomethylene Simvastatin (RRT 0.810)

Simvastatin Methyl Ester (RRT 1.100)

Dihydrosimvastatin (RRT 1.260)

Dehydrosimvastatin (RRT 2.669)

3-0-Mevinolinyl Simvastatin (RRT 3.945)

[0075] While the invention has been described and illustrated withreference to certain particular embodiments thereof, those skilled inthe art will appreciate that various changes, modifications andsubstitutions can be made therein without departing from the spirit andscope of the invention. It is intended, therefore, that the invention bedefined by the scope of the claims which follow and that such claims beinterpreted as broadly as is reasonable.

What is claimed is:
 1. A process for preparing a 3-hydroxylactone-containing product from its corresponding open-ring3,5-dihydroxy acid comprising the steps of: (i) adding a strong mineralacid to a stirring solution of the 3,5-dihydroxy acid in awater-miscible organic solvent, in an amount sufficient to lactonize the3,5-dihydroxy acid to form the 3-hydroxy lactone-containing product;(ii) adding an excess of additional strong mineral acid to the stirringreaction mixture in an amount sufficient to cause crystallization of the3-hydroxy lactone-containing product; (iii) collecting and washing the3-hydroxy lactone-containing product; and (iv) drying the washed3-hydroxy lactone-containing product.
 2. The process of claim 1 whereinthe water-miscible organic solvent is an aprotic solvent.
 3. The processof claim 2 wherein the water-miscible organic solvent is an aproticsolvent selected from the group consisting of acetonitrile,dimethylsulfoxide, dimethyl formamide, tetrahydrofuran and dioxane. 4.The process of claim 3 wherein the water-miscible organic solvent isacetonitrile.
 5. The process of claim 1 wherein the strong mineral acidused in steps (i) and (ii) is the same.
 6. The process of claim 1wherein the strong mineral acid is selected from the group consisting ofhydrochloric acid, hydrobromic acid, perfluoric acid, perchloric acid,phosphoric acid and nitric acid.
 7. The process of claim 6 wherein thestrong mineral acid is hydrochloric acid.
 8. The process of claim 7wherein the strong mineral acid is 4N hydrochloric acid.
 9. The processof claim 1 wherein from about 0.8 to 1.1 equivalents of strong mineralacid per each equivalent of open-ring 3,5-dihydroxy acid is used toeffect lactonization of the 3,5-dihydroxy acid.
 10. The process of claim1 wherein from about 2 to 5 equivalents of strong mineral acid per eachequivalent of 3-hydroxy lactone-containing product is used to causecrystallization of the lactone-containing product.
 11. The process ofclaim 1 wherein steps (i), (ii) and (iii) are performed at a temperatureof 10° C. or lower.
 12. The process of claim 1 wherein steps (i), (ii)and (iii) are performed at a temperature in the range from 10° C. to−15° C.
 13. The process of claim 1 wherein steps (i), (ii) and (iii) areperformed at a temperature in the range from −8° C. to −15° C.
 14. Theprocess of claim 1 wherein the 3,5- dihydroxy acid is treated withdecolorizing carbon followed by removal of the decolorizing carbonbefore proceeding to step (i).
 15. The process of claim 1 wherein thereaction mixture containing the 3-hydroxy lactone-containing product isseeded in order to promote crystal formation.
 16. The process of claim 1wherein the solvent used for the final wash of the collected product instep (iii) is comprised of about 0.1N to 0.5N strong mineral acid. 17.The process of claim 1 wherein the 3-hydroxy lactone-containing productis a statin in its lactone form.
 18. The process of claim 17 wherein thestatin has the structural formula III

wherein Y is a member selected from the group consisting of:

and wherein R is selected from —OH and —CH₃; and R′ is C₁₋₁₀ alkyl. 19.The process of claim 17 wherein the 3-hydroxy lactone-containing productis simvastatin.
 20. The process of claim 17 wherein the 3-hydroxylactone-containing product is lovastatin.
 21. The process of claim 17wherein the 3-hydroxy lactone-containing product is the lactonized formof a statin selected from the group consisting of pravastatin,fluvastatin, atorvastatin, cerivastatin, and nisvastatin.
 22. Theprocess of claim 1 for preparing a 3-hydroxy lactone-containing statinfrom its corresponding open-ring 3,5-dihydroxy acid comprising the stepsof: (i) adding 0.8 to 1.1 equivalents of strong mineral acid perequivalent of the 3,5- dihydroxy acid to a stirring solution of the 3,5-dihydroxy acid in an aprotic organic solvent to cause lactonization;(ii) adding an excess of additional strong mineral acid to the stirringreaction mixture in an amount sufficient to cause crystallization of the3-hydroxy lactone-containing product; (iii) collecting and washing the3-hydroxy lactone-containing product; and (iv) drying the washed3-hydroxy lactone-containing product; wherein steps (i), (ii) and (iii)are performed at a temperature of 10° C. or lower.
 23. The process ofclaim 22 wherein steps (i), (ii) and (iii) are performed at atemperature in the range from −8° C. to −15° C.
 24. The process of claim23 wherein statin is selected from lovastatin and simvastatin.
 25. Theprocess of claim 24 wherein the aprotic solvent is acetonitrile and thestrong mineral acid is hydrochloric acid.
 26. The process of claim 25wherein the 3-hydroxy lactone-containing product is simvastatin.
 27. Theprocess of claim 26 wherein from about 2 to 5 equivalents of strongmineral acid per each equivalent of simvastatin is used to causecrystallization in step (ii).
 28. The process of claim 27 wherein thesolvent used for the final wash of the collected product in step (iii)is comprised of about 0.1N to 0.5N hydrochloric acid.
 29. The process ofclaim 28 wherein the washed 3-hydroxy lactone-containing product isdried at a temperature in the range from 35° C. to 50° C.
 30. Theprocess of claim 1 further comprising an initial step of forming the3,5-dihydroxy acid by treating a salt of the 3,5-dihydroxy acid in awater-miscible organic solvent with a strong mineral acid in an amountsufficient to protonate the salt and form the corresponding3,5-dihydroxy acid.
 31. The process of claim 30 wherein the protonation,lactonization and crystallization steps are performed in a singlereaction pot.
 32. The process of claim 30 wherein the water-miscibleorganic solvent is an aprotic solvent.
 33. The process of claim 32wherein the water-miscible organic solvent is an aprotic solventselected from the group consisting of acetonitrile, dimethylsulfoxide,dimethyl formamide, tetrahydrofuran and dioxane.
 34. The process ofclaim 33 wherein the water-miscible organic solvent is acetonitrile. 35.The process of claim 30 wherein the same strong mineral acid is usedthroughout the process.
 36. The process of claim 30 wherein the strongmineral acid is selected from the group consisting of hydrochloric acid,hydrobromic acid, perfluoric acid, perchloric acid, phosphoric acid andnitric acid.
 37. The process of claim 36 wherein the strong mineral acidis hydrochloric acid.
 38. The process of claim 37 wherein the strongmineral acid is 4N hydrochloric acid.
 39. The process of claim 30wherein from about 0.8 to 1.1 equivalents of strong mineral acid pereach equivalent of open-ring 3,5-dihydroxy acid salt is used toprotonate the salt and form the corresponding 3,5-dihydroxy acid. 40.The process of claim 30 wherein from about 0.8 to 1.1 equivalents ofstrong mineral acid per each equivalent of open-ring 3,5-dihydroxy acidis used to effect lactonization of the 3,5-dihydroxy acid.
 41. Theprocess of claim 30 wherein from about 2 to 5 equivalents of strongmineral acid per each equivalent of 3-hydroxy lactone-containing productis used to cause crystallization of the lactone-containing product. 42.The process of claim 30 wherein the initial protonation step and thesubsequent steps (i), (ii) and (iii) are performed at a temperature of10° C. or lower.
 43. The process of claim 30 wherein the initialprotonation step and the subsequent steps (i), (ii) and (iii) areperformed at a temperature in the range from 10° C. to −15° C.
 44. Theprocess of claim 30 wherein the initial protonation step and thesubsequent steps (i), (ii) and (iii) are performed at a temperature inthe range from −8° C. to −15° C.
 45. The process of claim 30 wherein the3,5- dihydroxy acid is treated with decolorizing carbon followed byremoval of the decolorizing carbon before proceeding to step (i). 46.The process of claim 30 wherein the reaction mixture containing the3-hydroxy lactone-containing product is seeded in order to promotecrystal formation.
 47. The process of claim 30 wherein the solvent usedfor the final wash of the collected product is comprised of about 0.1Nto 0.5N strong mineral acid.
 48. The process of claim 30 wherein the3-hydroxy lactone-containing product is a statin in its lactone form.49. The process of claim 48 wherein the statin has the structuralformula III

wherein Y is a member selected from the group consisting of:

and wherein R is selected from —Oh and —CH₃; and R′ is C₁₋₁₀alkyl. 50.The process of claim 48 wherein the 3-hydroxy lactone-containing productis simvastatin.
 51. The process of claim 48 wherein the 3-hydroxylactone-containing product is lovastatin.
 52. The process of claim 48wherein the 3-hydroxy lactone-containing product is the lactonized formof a statin selected from the group consisting of pravastatin,fluvastatin, atorvastatin, cerivastatin, and nisvastatin.
 53. A processfor preparing a 3-hydroxy lactone-containing statin from a salt of itscorresponding open-ring 3,5-dihydroxy acid comprising the steps of: (i)adding 0.8 to 1.1 equivalents of strong mineral acid per equivalent of3,5-dihydroxy acid salt to a stirring mixture of the 3,5-dihydroxy acidsalt in an aprotic organic solvent to protonate the salt and form thecorresponding 3,5-dihydroxy acid; (ii) adding 0.8 to 1.1 equivalents ofstrong mineral acid per equivalent of 3,5-dihydroxy acid to the stirringreaction mixture to cause lactonization; (iii) adding an excess ofadditional strong mineral acid to the stirring reaction mixture in anamount sufficient to cause crystallization of the 3-hydroxylactone-containing product; (iv) collecting and washing the 3-hydroxylactone-containing product; and (v) drying the washed 3-hydroxylactone-containing product; wherein steps (i), (ii), (iii) and (iv) areperformed at a temperature of 10° C. or lower.
 54. The process of claim53 wherein steps (i), (ii), (iii) and (iv) are performed at atemperature in the range from −8° C. to −15° C.
 55. The process of claim54 wherein the statin is selected from lovastatin and simvastatin. 56.The process of claim 55 wherein the salt of the statin is the ammoniumsalt.
 57. The process of claim 55 wherein the aprotic solvent isacetonitrile and the strong mineral acid is hydrochloric acid.
 58. Theprocess of claim 57 wherein the 3-hydroxy lactone-containing product issimvastatin.
 59. The process of claim 58 wherein from about 2 to 5equivalents of strong mineral acid per each equivalent of simvastatin isused to cause crystallization in step (iii).
 60. The process of claim 59wherein the solvent used for the final wash of the collected product instep (iv) is comprised of about 0.1N to 0.5N hydrochloric acid.
 61. Theprocess of claim 60 wherein the washed 3-hydroxy lactone-containingproduct is dried at a temperature in the range from 35° C. to 50° C. instep (v)
 62. The process of claim 53 wherein the 3,5- dihydroxy acid istreated with decolorizing carbon followed by removal of the decolorizingcarbon before the lactonization step.
 63. The process of claim 53wherein the reaction mixture containing the 3-hydroxy lactone-containingproduct in step (iii) is seeded in order to promote crystal formation.64. A commercial scale composition comprised of a 3-hydroxylactone-containing product absent 3-O-acylated impurities, and 0.20 area% or less of dimeric impurity.
 65. The commercial scale composition ofclaim 64 comprising from 0.20 to 0.01 area % of dimeric impurity. 66.The commercial scale composition of claim 64 comprised of 0.1 area % orless of dimeric impurity.
 67. The commercial scale composition of claim66 comprising from 0.1 to 0.01% area of dimeric impurity.
 68. Thecommercial scale composition of claim 66 comprised of a 3-hydroxylactone-containing product absent 3-O-acylated impurities, 0.1 area % orless of dimeric impurity, and 0.1 area % or less of each of the otherimpurities present in the composition.
 69. The commercial scalecomposition of claim 68 comprising from 0.1 to 0.01 area % of dimericimpurity and from 0.1 to 0.01 area % of each of the other impuritiespresent in the composition.
 70. The commercial scale composition ofclaim 66 comprised of a 3-hydroxy lactone-containing product absent3-O-acylated impurities, 0.1 area % or less of dimeric impurity, 0.1area % or less of 3-exomethylene simvastatin, and 0.10 area % or less ofeach of the other impurities present in the composition.
 71. Thecommercial scale composition of claim 70 comprising from 0.1 to 0.01area % of dimeric impurity, 0.1 to 0.01 area % of 3-exomethylenesimvastatin, and 0.10 to 0.01 area % of each of the other impuritiespresent in the composition.
 72. The commercial scale composition ofclaim 66 comprised of 0.10 area % or less of dimeric impurity.
 73. Thecommercial scale composition of claim 68 comprised of 0.10 area % orless of dimeric impurity.
 74. The commercial scale composition of claim70 comprised of 0.10 area % or less of dimeric impurity.
 75. Thecommercial scale composition of claim 64 wherein the 3-hydroxylactone-containing product is a statin in its lactone form.
 76. Thecommercial scale composition of claim 75 wherein the statin islovastatin.
 77. The commercial scale composition of claim 75 wherein thestatin is simvastatin.
 78. A commercial scale composition comprised ofsimvastatin, 0.1 area % or less of simvastatin dimer, and 0.00 area % of3-O-acetyl simyastatin and 3-O-acetyl 5-hydroxy acid simvastatin. 79.The commercial scale composition of claim 78 comprised of simvastatin,0.1 area % or less of simvastatin dimer, 0.00 area % of 3O-acetylsimvastatin and 3-O-acetyl 5-hydroxy acid simvastatin, and 0.1 area % orless of each of the other impurities present in the composition.
 80. Thecommercial scale composition of claim 79 comprised of simvastatin, 0.1area % or less of simvastatin dimer, 0.00 area % of 3-O-acetylsimvastatin and 3-O-acetyl 5-hydroxy acid simvastatin, 0.1 area % orless of 3-exomethylene simvastatin, and 0.10 area % or less of each ofthe other impurities present in the composition.
 81. The commercialscale composition of claim 78 comprised of 0.10 area % or less ofsimvastatin dimer.
 82. The commercial scale composition of claim 79comprised of 0.10 area % or less of simvastatin dimer.
 83. Thecommercial scale composition of claim 80 comprised of 0.10 area % orless of simvastatin dimer.